Aggregation of activated platelets on ruptured or eroded atherosclerotic plaques initiates thromboses of the arterial system, resulting in ischemic syndromes. The propensity of platelets to aggregate in vivo can be well characterized by in vitro assays, which can be then used to identify individuals with hyper-aggregable platelets who are at risk for myocardial infarction, stroke, and peripheral arterial occlusions. Over the past decade, in an ongoing NHLBI-funded study called GeneSTAR (Genetic Study of Atherosclerotic Risk), and through a collaborative effort including the Old Order Amish Study and Framingham Heart Study (FHS), genome-wide association studies (GWAS) revealed multiple common genetic loci that determine platelet aggregation. Collectively, the loci identified through this common variant approach account for less than 35% of the total heritability in these phenotypes, and furthermore, the causal variants for these loci are poorly understood or unknown. Leveraging data acquired through three independent pre-existing grants within the GeneSTAR Program we have a unique opportunity to perform integrative multi-omic analyses of DNA and RNA sequencing data beyond the scope of traditional genetic association studies, to address two current gaps in our understanding of platelet aggregation: (1) identify the causal variant(s) for the previously detected loci; and, (2) uncover the genetic determinants of high residual heritability missed thus far through this siloed single-omic genetic approach. In response to RFA-HL-19-020 we will perform a set of integrative analyses within the GeneSTAR families to (i) define the regulatory signature of all sequence variants that are relevant for platelet aggregation; (ii) elucidate the biological mechanisms for known genetic loci associated with platelet aggregation; and (iii) identify genetic determinants that account for residual heritability in platelet aggregation. We will replicate our discoveries of residual heritability in the FHS and the Amish Study, both members of an active working group with harmonized phenotypes within TOPMed along with GeneSTAR. This application, productively integrating our genomic and transcriptomic analyses in both European American and African American cohorts, will yield new genetic loci contributing to the missing heritability in platelet aggregation, and provide biological insights linking genetic variants and platelet function within a gene network/pathway framework. The identification and ultimate functional understanding of meaningful genetic determinants for platelet aggregation has widespread significance and would contribute to improved antiplatelet therapies that could be tailored to individuals based on their genetic profiles within a precision medicine framework.